The present invention is directed to the use of a class of peptide compounds for treating diseases associated with hyperexcitability, such as diseases associated with a hyperexcitable tissue. The present invention is also directed to the use of a class of peptide compounds for treating diseases associated with dysfunction of an ion channel.
Certain peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS disorders. These peptides are described in the U.S. Pat. No. 5,378,729 and in U.S. Pat. No. 5,773,475, which are hereby incorporated by reference.
WO 02/074297 relates to the use of peptidic compounds for the preparation of pharmaceutical compositions useful for the treatment of allodynia related to peripheral neuropathic pain. WO 02/074784 relates to the use of peptidic compounds showing antinociceptive properties for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain, e.g. rheumatoid arthritic pain or/and secondary inflammatory osteo-arthritic pain.
According to their mode of regulation, ion channels can be divided into voltage-gated ion channels and ligand-gated ion channels. Ligand-gated ion channels are also referred to as receptors. Examples for voltage-gated ion channels are voltage-gated sodium channels, voltage-gated calcium channels, voltage-gated potassium channels, and voltage-gated chloride channels. Examples for ligand-gated ion channels are nicotinic acetylcholine receptors, ryanodine receptors (calcium release channels), cyclic nucleotide-gated receptors, ATP-receptors, GABA-A receptors, glutamate-NMDA receptors, glycine-receptors, 5-HT3-receptors, and pH sensitive channels such as acid-sensing ion channel (ASIC), and TRP receptors.
Hyperexcitability is defined herein as an abnormal increase in responsiveness of a central or peripheral nervous system neuron to synaptic input. In addition, hyperexcitability is also referred to as an abnormal increase in responsiveness of any excitable membrane, such as a muscle cell membrane, to a physiological signal or to excitotoxicity caused by a pathophysiological signal.
Examples for hyperexcitable tissues are all innervated tissues such as central or peripheral nervous tissue, muscle tissue, and other organ tissue.
Examples for diseases associated with hyperexcitability are channelopathies, anxiety- and stress-diseases.
Hyperexcitability can be induced by dysfunction of ion channels. According to their mode of regulation, ion channels can be divided into voltage-gated ion channels and ligand-gated ion channels. Ligand-gated ion channels are also referred to as receptors. Examples for voltage-gated ion channels are voltage-gated sodium channels, voltage-gated calcium channels, voltage-gated potassium channels, and voltage-gated chloride channels. Examples for ligand-gated ion channels are nicotinic acetylcholine receptors, ryanodine receptors (calcium release channels), cyclic nucleotide-gated receptors, ATP-receptors, GABA-A receptors, glutamate-NMDA receptors, glycine-receptors, 5-HT3-receptors, and pH sensitive channels such as acid-sensing ion channel (ASIC), and TRP receptors.
Ion channel dysfunction may have genetic or other causes, such as tissue damage.
Diseases caused by one or more mutations of genes coding for ion channel subunits or proteins that regulate them are referred to as channelopathies. There are a large number of distinct dysfunctions known to be caused by ion channel mutations. They comprise a heterogenous group of usually hereditary disorders which in most cases are clinically characterized by episodes of disturbed excitability of nerve or muscle cells. The genes for the construction of ion channels are highly conserved amongst mammals and one condition, hyperkalemic periodic paralysis, was first identified in the descendants of Impressive, a pedigree race horse. Well known examples of identified channelopathies are diseases of the skeletal muscle (such as hyper-, hypo- and normokalemic (high, low and normal potassium blood concentrations) periodic paralysis, paroxysmal dystonia, myotonia congenita and paramyotonia congenita), central nervous disorders of excitability (such as episodic ataxias and several forms of inherited epilepsies), and cardiac arrhythmias (such as long QT syndromes).
Ion channels dysfunctions can also be caused by variations in ion channel genes that are not sufficiently severe to be classified as mutations, but instead are referred to as polymorphisms. Such polymorphisms may contribute to unique drug responses in carriers of these gene variants (Kass, R S, J Clin Invest (2005), 115:1986-1989).
Voltage-gated sodium channels are responsible for the generation and propagation of action potentials in excitable cells. The excitability of tissues depends mainly on the number of voltage-gated sodium channels that are available for activation. The fraction of sodium channels available for activation is regulated by fast inactivation, which occurs on a millisecond time scale, and slow inactivation occurring within seconds or minutes.
Mutations in genes coding for sodium channels are known to cause a number of characteristic diseases. Most inherited sodium channel mutations that are associated with human disease alter the inactivation process and hence alter the essential control of electrical-impulse duration that is effected by transition into the inactivated state (Jurkat-Rott, K, J Clin Invest (2005), 115:2000-2009). Most well characterised mutations are at the SCN4A sodium channel gene which codes for the alpha-subunit of the skeletal muscle sodium channel. Following diseases are listed in the OMIM database of NCBI for the SCN4A gene:                Cramps, familial, potassium-aggravated MIM: 603967        Hyperkalemic periodic paralysis MIM: 170500        Hypokalemic periodic paralysis MIM: 170400        Myotonia congenita, atypical, acetazolamide-responsive MIM: 608390        Paramyotonia congenita MIM: 168300.        
Dystonia (literally, “abnormal muscle tone”) is a generic term used to describe a neurological movement disorder involving involuntary, sustained muscle contractions. Dystonia may affect muscles throughout the body (generalised), in certain parts of the body (segmental), or may be confined to particular muscles or muscle groups (focal). Primary dystonia is caused by a pathology of the central nervous system, likely originating in those parts of the brain concerned with motor function, such as the basal ganglia. An example for dystonia associated with dysfunction of the voltage-gated sodium channel is paroxysmal dystonia.
Muscle weakness (or “lack of strength”) is the inability to exert force with ones muscles to the degree that would be expected given the individual's general physical fitness. A test of strength is often used during a diagnosis of a muscular disorder before the etiology can be identified.
The term subsumes two other more specific terms, true weakness and perceived weakness. True weakness (or “objective weakness”) describes a condition where the instantaneous force exerted by the muscles is less than would be expected. For instance, if a patient suffers from amyotrophic lateral sclerosis (ALS), motor neurons are damaged and can no longer stimulate the muscles to exert normal force. Perceived weakness (or “subjective weakness”) describes a condition where it seems to the patient that more effort than normal is required to exert a given amount of force. For instance, a person with chronic fatigue syndrome may struggle to climb a set of stairs when feeling especially fatigued, but if their muscle strength is objectively measured (eg, the maximum weight they can press with their legs) it is essentially normal. In some conditions such as myasthenia gravis muscle strength is normal when resting, but true weakness occurs after the muscle has been subjected to exercise.
Myotonia is a neuromuscular disorder characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed-up. However, prolonged, rigorous exercise may also trigger the condition. Individuals with the disorder may have trouble releasing their grip on objects or may have difficulty rising from a sitting position and a stiff, awkward gait. During pregnancy, symptoms of myotonia are more frequently experienced in women.
Myotonia can affect all muscle groups. It may be acquired or inherited, and is caused by an abnormality in the muscle membrane. Myotonia is a symptom commonly seen in patients with myotonic muscular dystrophy and channelopathies. Myotonia arising from channelopathies can be exacerbated by exposure to cold, by eating foods that are potassium-rich (such as bananas), and with exertion.
Myasthenias are a group of disorders which exhibit several striking features the essential one being a fluctuating weakness and fatigability of muscle. There is usually some degree of weakness at all times but it is made worse by activity. The weakness and fatigability reflect physiologic abnormalities of the neuromuscular junction that are demonstrated by clinical signs and special electrophysiologic testing.
Paralysis is the complete loss of muscle function for one or more muscle groups. Major causes are stroke, trauma, poliomyelitis, amyotrophic lateral sclerosis (ALS), botulism, spina bifida, and Guillain-Barré syndrome. Paralysis is most often caused by damage to the nervous system or brain, especially the spinal cord. Paralysis often includes loss of feeling in the affected area.
Paramyotonia Congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct. Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked-off, in contrast to myotonia congenita. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia and/or weakness. Typical presentations of this are during squating or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrots and watermelon are able to induce these symptoms. The canonical definition of this disorder precludes permenant weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature. Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise/movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. Electromyography may be used to distinguish between paramyotonia congenita and myotonia congenita. Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis, or one of the potassium-aggravated myotonias. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.
Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others, however, require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of mytonia prevention.
Paramyotonia congenita (as well as hyperkalemic periodic paralysis and the potassium-aggravated myotonias) is caused by mutations in SCN4A. The phenotype of patients with these mutations is indicated in Table 1 below. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channel's kinetics.
TABLE 1Mutations of SCN4A (adapted from Vicart et al., 2005).Mutation region nomenclature is: domain number (e.g., D1) followed bysegment number (e.g., S4). Thus, D2S3 indicates that the mutation is inthe 3rd membrane spanning loop of the 2nd domain. Some mutationsoccur between segments and are denoted similarly (e.g., D4S4-S5 occursbetween the 4th and 5th segments of the 4th domain). Other mutations arelocated between domains and are denoted DX-Y where X and Y aredomain numbers. C-term refers to the carboxy-terminus.MutationRegionI693TD2S4-S5T704M*D2S5S804F**D2S6A1152DD3S4-S5A1156T*D3S4-S5V1293ID3S4G1306V**D3-4T1313AD3-4T1313MD3-4M1360V*D4S1M1370V*D4S1L1433RD4S3R1448CD4S4R1448HD4S4R1448PD4S4R1448SD4S4R1456ED4S4V1458FD4S4F1473SD4S4-S5M1592V*D4S6G1702KC-termF1795IC-term*Symptoms of both PC and hyperKPP (Periodica paralytica paramyotonica)**Also diagnosed as a Potassium-aggravated myotonia
Diseases associated with hyperexcitability or/and diseases associated with dysfunction of an ion channel might be caused by genetic dysfunction of voltage- or ligand-gated ion channels, such as voltage-gated calcium channels, voltage-gated potassium channels, voltage-gated chloride channels, nicotinic acetylcholine receptors, ryanodine receptors (calcium release channels), cyclic nucleotide-gated receptors, ATP-receptors, GABA-A receptors, glutamate-NMDA receptors, glycine-receptors, 5-HT3-receptors, and pH sensitive channels such as acid-sensing ion channel (ASIC), and TRP receptors. Diseases associated with dysfunction of these ion channels include, among others, ataxias, myotonias, myasthenias, long QT syndromes, epilepsy syndromes, and hyperthermia.
Examples for further diseases associated with hyperexcitability that might be caused by other reasons than mutations and polymorphisms in genes coding for ion channel subunits or proteins that regulate them are anxiety and stress. Stress and other anxiogenic stimuli can cause hyperexcitability of amygdala neurones (Rainnie et al. J Neuroscience 2004 24(14):3471-3479). Since the amygdala is a key brain center for emotion acute severe or chronic mild stress can result in persistent changes in emotion as for instance found in patients suffering from post-traumatic stress disorder.
Lacosamide does not exert its effects on neuronal excitability by affecting fast inactivation gating of voltage-gated Na+ channels (Errington et al., Neuropharmacology, 2006, 50:1016-1029).